1. Field of the Invention
The present invention is directed to the treatment of non-infectious, non-neoplastic inflammatory conditions of the central nervous system using high dose methotrexate treatments.
2. Description of Related Art
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) with unknown cause and no known cure. Though single episodes of demyelination can occur, once the disease is established in multiple sites in the brain, spinal cord, and optic nerves, MS frequently follows a clinically relapsing-remitting course while lesions in the CNS continue to progress. During this phase, an immune mediated inflammatory response to myelin antigens is thought to play a major role in the pathogenesis of developing lesions. Then, in a clinically progressive phase, at least fifty-five percent of patients worsen, with clinical relapses sometimes punctuating their clinical decline.
The mechanism of tissue damage to the CNS is not known with certainty in the progressive phase of MS. It is thought, however, that axonal damage, perhaps through some type of immune mediation, is important in this phase of the disease, though some axonal damage certainly occurs during the inflammatory phase.
Perivascular infiltration of T lymphocytes and macrophages in brain lesions is one of the characteristics of MS. Activation of myelin-reactive T cells in the periphery is an early event in the MS process. These activated T cells facilitate the production by B cells of antibodies against myelin, and activate macrophages to attack oligodendrocytes in the CNS. The functions of these immune cells are regulated by cytokines in autocrine and paracrine fashions. Pro-inflammatory cytokines like IFN-γ, and TNF-α could have disease-promoting roles in MS, whereas anti-inflammatory cytokines, like IL-4, IL-10 and TGF-β, likely down-regulate the disease. The balance between pro-inflammatory and anti-inflammatory cytokines may determine the outcome of injury in MS.
Treatment options for patients with MS are limited. Currently, the primary drugs used to treat MS are interferons and glatiramer acetate. These drugs are marketed under the brand names AVONEX by Biogen, Inc. (interferon-beta-la, recombinant), BETASERON by Berlex Laboratories, Inc. (interferon-beta-1b, recombinant) and CAPOXONE by Teva Neuroscience, LLC (copolymer-1, glatiramer acetate), and are often referred to as the “ABC” treatments. Such treatments have been shown to slow, but not arrest, the clinical course of progression in progressive MS. Thus, alternative, or backup, treatment methods are needed.
Certain chemotherapeutic agents, such as methotrexate, mitoxantrone and cyclophosphamide, have been used to treat MS. Although mitoxantrone and cyclophosphamide have shown some efficacy against the progression of MS, they do not cross the blood brain barrier (BBB) into the CNS and mitoxantrone has limited lifetime use due to toxicity.
Methotrexate is an S-phase chemotherapeutic anti-metabolite, used for the treatment of various neoplasms, particularly CNS lymphoma. Methotrexate is also an anti-inflammatory agent and has been used for the treatment of various autoimmune diseases, such as rheumatoid arthritis and psoriasis. Methotrexate is a folate analogue which competitively binds and inhibits dihydrofolate reductase (DHFR), and thus inhibits the synthesis of thymidine and other compounds requiring methylation for their synthesis by inhibiting the single carbon transfer necessary for their synthetic pathways. Methotrexate also promotes the release of adenosine, and this mechanism may be responsible for its anti-inflammatory activity.
Clinical trials using low-dose methotrexate (7.5 mg/week), administered orally, in progressive MS, have been shown to impact the course of progressive MS with minimal toxicity. This treatment option has been widely adopted in the United States for MS patients in the progressive phase who are developing upper extremity dysfunction. Some MS centers empirically treat refractory patients with higher doses (15 mg or 20 mg) orally once a week. However, when administered orally, the serum level of methotrexate is not sufficient to cross the BBB in cytotoxic amounts. Thus, while oral methotrexate treatments show mild improvement in upper extremity strength in MS patients, a need remains for a treatment that arrests or reverses the progression of the disease.
Methotrexate has been given intravenously in high enough doses to cross the blood-brain barrier (BBB) and enter the CNS. The peripheral bone marrow, immune system, gastrointestinal endothelium and other vital rapidly dividing tissues can be rescued by an inhibitor of methotrexate, such as leucovorin, which does not penetrate the BBB. The safety of high dose methotrexate therapy with leucovorin rescue has been demonstrated. For example, clinical trials using high dose methotrexate (8 g/m2), administered via a four hour intravenous (IV) infusion, with leucovorin rescue, have shown promising results in treating CNS lymphomas with low toxicity. High dose methotrexate (2.5 g/m2) sporadically administered via IV infusion, with leucovorin rescue, has similarly shown no significant toxicity. Further, it is believed no cumulative deficit from repeated treatments has been reported.